This proposal describes a study of the mu opioid receptor (OPRM1) gene in two strains of mice (C57B1/6J and DBA/2J) which differ remarkably in voluntary morphine intake during a two-bottle choice paradigm. Quantitative trait loci mapping revealed that a segment of proximal murine chromosome 10 determines nearly 50 percent of the genetic variance in voluntary morphine consumption. The OPRM1 gene was subsequently mapped to this region. To study OPRM1 function in the rewarding aspects of opioids, reciprocal congenic strains are being created. A C57B1/6J chromosome 10 interval (containing the OPRM gene) is being bred onto a DBA/2J background. Similarly, the DBA/2J chromosome 10 interval is being transferred to a C57B1/6J background. In addition, OPRM1 null mutant mice on C57Bl/6J and DBA/2J backgrounds are being prepared. D2 transgenic mice, expressing the B6 OPRM1 allele are being created. These groups of genetically unique mice will be compared with the parental strains (C57B1/6J and DBA/2J) for several phenotypes which assess the rewarding properties of opioids. These phenotypes include operant intravenous morphine self-administration, voluntary two- bottle choice morphine drinking and morphine place preference. Differences among genetically unique groups of mice and parental inbred strains may increase our understanding of the OPRM1 role in rewarding properties of opioids. This may enhance our knowledge of genetic susceptibility to opioid dependence in human populations.